Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells

被引:199
作者
Wang, Yue [1 ,2 ]
Niu, Xiu Long [1 ]
Qu, Ye [3 ]
Wu, Jian [1 ]
Zhu, Ya Qin [1 ]
Sun, Wei Jia [1 ]
Li, Ling Zhi [2 ,4 ]
机构
[1] Med Coll Chinese Peoples Armed Police Forces, Dept Immunol, Tianjin 300162, Peoples R China
[2] Tianjin Key Lab Biomarkers Occupat & Environm Haz, Tianjin, Peoples R China
[3] Med Coll Chinese Peoples Armed Police Forces, Dept Microbiol, Tianjin 300162, Peoples R China
[4] Med Coll Chinese Peoples Armed Police Forces, Dept Pharmaceut Chem, Tianjin 300162, Peoples R China
关键词
Interleukin-6 (IL-6); Chemoresistance; Multidrug resistance-related genes; Apoptosis inhibitory proteins; Ovarian cancer; REGULATED PROTEIN-KINASE; X-LINKED INHIBITOR; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; IN-VITRO; CARCINOMA-CELLS; INCREASES EFFICACY; APOPTOSIS PROTEIN; GENE-EXPRESSION; UP-REGULATION;
D O I
10.1016/j.canlet.2010.02.019
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
It has been shown that IL-6 is elevated in the serum and ascites of ovarian cancer patients, and increased IL-6 concentration correlates with poor prognosis and chemoresistance. However, the role of IL-6 expression in the acquisition of the chemoresistance phenotype and the underlining mechanisms of drug resistance in ovarian cancer cells remain unclear. Here we demonstrate that both exogenous (a relatively short period of treatment with recombination IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) induce cisplatin and paclitaxel resistance in non-IL-6-expressing A2780 cells, while deleting of endogenous IL-6 expression in IL-6-overexpressing SKOV3 cells (by transfecting with plasmid encoding for antisense IL-6) promotes the sensitivity of these cells to anticancer drugs. IL-6-mediated resistance of ovarian cancer cells exhibits decreased proteolytic activation of caspase-3. Meanwhile, the further study demonstrates that the chemoresistance caused by IL-6 is associated with increased expression of both multidrug resistance-related genes (MDR1 and GSTpi) and apoptosis inhibitory proteins (Bc1-2, Bcl-xL and XIAP), as well as activation of Ras/MEK/ERK and PI3K/Akt signaling. Therefore, modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for drug-resistant ovarian cancer. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:110 / 123
页数:14
相关论文
共 60 条
[1]   Ovarian cancer: Strategies for overcoming resistance to chemotherapy [J].
Agarwal, R ;
Kaye, SB .
NATURE REVIEWS CANCER, 2003, 3 (07) :502-516
[2]   Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin [J].
Arimoto-Ishida, E ;
Ohmichi, M ;
Mabuchi, S ;
Takahashi, T ;
Ohshima, C ;
Hayakawa, J ;
Kimura, A ;
Takahashi, K ;
Nishio, Y ;
Sakata, M ;
Kurachi, H ;
Tasaka, K ;
Murata, Y .
ENDOCRINOLOGY, 2004, 145 (04) :2014-2022
[3]  
Asschert JGW, 1999, INT J CANCER, V82, P244, DOI 10.1002/(SICI)1097-0215(19990719)82:2<244::AID-IJC15>3.0.CO
[4]  
2-N
[5]   MODULATION OF CISPLATIN CYTOTOXICITY BY SULFASALAZINE [J].
AWASTHI, S ;
SHARMA, R ;
SINGHAL, SS ;
HERZOG, NK ;
CHAUBEY, M ;
AWASTHI, YC .
BRITISH JOURNAL OF CANCER, 1994, 70 (02) :190-194
[6]  
Baekelandt MM, 2000, ANTICANCER RES, V20, P1061
[7]  
BORSELLINO N, 1995, CANCER RES, V55, P4633
[8]   Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells [J].
Chauhan, D ;
Kharbanda, S ;
Ogata, A ;
Urashima, M ;
Teoh, G ;
Robertson, M ;
Kufe, DW ;
Anderson, KC .
BLOOD, 1997, 89 (01) :227-234
[9]  
Conze D, 2001, CANCER RES, V61, P8851
[10]   STATs and gene regulation [J].
Darnell, JE .
SCIENCE, 1997, 277 (5332) :1630-1635